NOVEL NONPEPTIDE LIGANDS FOR THE OPIOID RECEPTORS

描述(改编自申请人的摘要)： 这个项目的长期目标是小说的发展 具有阿片类药物特异性激动剂或拮抗剂活性的非肽配体 具有潜在药用价值的受体及其亚型 作为工具和治疗剂。大量证据表明， 阿片受体参与脊髓和棘上神经的调节 抗伤害性作用及对止痛药、耐受性和依赖性的影响 吗啡等()激动剂的作用。在我们的合作努力中，我们有 发现杂芳环融合的吗啡，如 吡哆醇单胞菌可以作为小说发展的模板 阿片受体的高亲和力配体(GAMA)，以及战略 在该骨架上放置芳香族取代基不仅可以提供 强效的o受体拮抗剂，但也有具有拉尼克斯(GAMA)的配体 拮抗剂/()激动剂性质。对具有这种混合()的化合物的兴趣 激动剂/(GAMA)拮抗剂的性质从最近的耐受性来看，表明 它们具有作为新型止痛药的潜力，没有耐受性和 依赖副作用。 本文提出的研究的一个主要目标是追求设计、综合 以及基于具有特定结构的先导化合物的新型配体的评价 (A)用()激动剂的平衡轮廓识别配基的目的 拮抗剂性质，(B)识别具有上级(GAMA)拮抗剂的配体 比原型更有选择性，以及(C)发展结构-活性 相互关系，以深入了解配体-受体相互作用。新的 要研究的配体涉及对铅结构的合理修饰 包括系统取代基的变化，介绍了 构象限制及取代效应的探讨 通过合成srnall的立体耐受位置，聚焦 化合物的资料库。将对这些化合物进行的评估 将包括：(I)评价放射性配基中阿片受体的结合亲和力 结合试验(II)体外生化药效评价 测定和(Iii)体内药理学评价以描述止痛剂， 前景看好的配体的耐受性和依赖性效应。这一全面的 方法应导致识别和开发能够 为慢性疼痛的治疗和患者提供新的方法 与滥用药物有关的问题。

DESCRIPTION(Adapted from applicant's abstract): The long term objectives of this project are the development of novel nonpeptide ligands with specific agonist or antagonist activity at the opioid receptors and their subtypes with the potential for use as phamtacological tools and as therapeutic agents. A large body of evidence indicates that the opioid & receptors are involved in mediating spinal and supraspinal antinociception, and in rnodulating the analgesic and tolerance and dependence effects of () agonists such as morphine. In our collaborative effort we have discovered that heteroaromatic ring-fused morphinans such as the pyridomorphinans can serve as suitable templates for the development of novel high affmity ligands for the opioid (gama)receptors, and that strategic placement of aromatic substituents on this framework can provide not only potent o receptor antagonists, but also ligands possessing rnixed (gama) antagonist/() agonist properties. Interest in compounds with such mixed () agonist/ (gama) antagonist properties stans from recent endence indicating that they have the potential to ernerge as novel analgesics devoid of tolerance and dependence side effects. A major goal of the research proposed herein is to pursue the design, synthesis and evaluation of novel ligands based on the lead compounds with the specific aims of (A) identifying ligands with a balanced profile of () agonistl o antagonist properties, (B) identifying ligands with superior (gama) antagonist selectivity than the prototypes, and (C) developing structure-activity correlations to gain an insight into ligand-receptor interactions. The new ligands to be pursued involve rational modifications to the lead structures including systernatic substituent group variations, introduction of conformational restraints as well as exploration of effect of substitutions at sterically tolerant positions thTough the synthesis of srnall, focused libraries of compounds. The evaluations to be carried out on these compounds will include (i) evaluation of opioid receptor binding affmities in radioligand binding assays (ii) evaluation of efficacy profile in vitro in biochemical assays and (iii) phannacological evaluations in vivo to profile analgesic, tolerance and dependence effects of promising ligands. This comprehensive approach should lead to the identification and development of drugs that could provide new approaches to the treatment of chronic pain and for the teatrnent of problems associated with drugs of abuse.